Abstract The myeloproliferative neoplasms (MPNs) are chronic hematological malignancies originating at the level of the pluripotent hematopoietic stem cell (HSC). This unique assembly of both laboratory and clinical MPN investigators coupled with the infrastructure to conduct independent, investigator-initiated, multicenter, trials has proven to be rewarding over the last 10 years of continuous NCI-funding and is poised to continue to further evolve. Keeping in mind the constructive reviewer comments, we have concentrated our clinical efforts into a stronger and more nimble consortium of 9 core clinical sites based solely in North America with established centers of excellence in MPN. The new application for Project 4 (formerly Project 6) is focused on myelofibrosis (MF) the MPN with the most limited survival and the clinical translation of mechanism based therapeutics derived from disease targets identified in Projects 1-3. An initial wave of early phase, single agent clinical trials (MPN-RC 116-118) will be conducted in years 1-3 and then three innovative combination therapy trials derived from supportive pre-clinical data and single agent tolerability and signal of activity will be pursued in years 3-5 (MPN-RC 119-123). Additionally, primary MPN tissue will be acquired through the MPN-RC tissue procurement protocol (Core B) and genomically characterized (Core D) from patients seen at all sites for distribution to Projects 1-3. Each trial will also have study schedule-specific, protocol driven, biomarkers to determine 1) effect on MPN HSC burden through mutational and cytogenetic analysis; 2) confirmation of proposed therapeutic mechanism of action through drug specific pharmacodynamic studies; 3) restoration of normal bone marrow microenvironment through histomorphologic analysis and cytokine expression profiles. The overarching goal of Project 4 is to test agents and innovative approaches that alone or in combination delete the MF HSC and favorably modify the MF-supporting microenvironment, thereby, altering the natural history of MF and improving patient outcome. The specific aims include 1) Annually obtain peripheral blood from MF patients in order to provide molecularly characterized tissue specimens that will be utilized for the investigations planned in Projects 1-3; 2) Conduct early phase clinical trials years 1-3 utilizing agents targeting the MPN HSC that have mechanistic rationales originating from Projects 1-3; 3) Evaluate therapeutic agents in early phase clinical trials years 1-3 that can interrupt the MF HSC supporting tumor microenvironments and, thereby, restore a bone marrow niche favoring normal hematopoiesis; 4) Utilize agents from Phase I/II trials associated with Aims 2 and 3 that can be tested in combination therapy approaches in years 3-5. The close interaction among the scientific projects, biostatistical, administrative, tissue bank, and biomarker cores with Project 4 embodies the true potential for translational research in MF that only the MPN-RC can provide.